Human immunodeficiency virus type 1 Nef protein mediates neural cell death: a neurotoxic role for IP-10
| Autor: | Justin C. McArthur, Scot D. Henry, Claudia Silva, M. John Gill, Guido van Marle, Janet Holden, Sean B. Rourke, Tiona R. Todoruk, Andrea Sullivan, Christopher Power |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Programmed cell death Sindbis virus AIDS Dementia Complex viruses Genetic Vectors Interleukin-1beta Molecular Sequence Data Neurotoxins Mice SCID CXCR3 Gene Products nef Animals Genetically Modified Mice Mice Inbred NOD Virology medicine Cytotoxic T cell Animals Humans RNA Messenger nef Gene Products Human Immunodeficiency Virus Neuroinflammation Cells Cultured Chemokine CCL2 NOD mice Neurons Nef biology Cell Death HIV-1-associated dementia virus diseases Neuron biology.organism_classification Molecular biology Peptide Fragments Recombinant Proteins Chemokine CXCL10 medicine.anatomical_structure Astrocytes HIV-1 Chemokines CXC Astrocyte Interleukin-1 |
| Zdroj: | Virology. 329(2):302-318 |
| ISSN: | 0042-6822 |
| DOI: | 10.1016/j.virol.2004.08.024 |
| Popis: | HIV-1 Nef is expressed in astrocytes, but a contribution to neuropathogenesis and the development of HIV-associated dementia (HAD) remains uncertain. To determine the neuropathogenic actions of the HIV-1 Nef protein, the brain-derived (YU-2) and blood-derived (NL4-3) Nef proteins were expressed in neural cells using an alphavirus vector, which resulted in astrocyte death (P < 0.001). Supernatants from Nef-expressing astrocytes also caused neuronal death, suggesting the release of neurotoxic molecules by astrocytes. Analysis of pro-inflammatory gene induction in astrocytes expressing Nef revealed increased IP-10 mRNA expression (4000-fold) that was Nef sequence dependent. Recombinant IP-10 caused selective cell death in neurons (P < 0.001) but not astrocytes, and the cytotoxicity of supernatant from astrocytes expressing Nef YU-2 was blocked by an antibody directed against the chemokine receptor CXCR3 (P < 0.001). SCID/NOD mice implanted with a Nef YU-2-expressing vector displayed abnormal motor behavior (P < 0.05), neuroinflammation, and neuronal loss relative to controls. Analysis of mRNA levels in brains from patients with HAD also revealed increased expression of IP-10 (P < 0.05), which was confirmed by immunoreactivity detected principally in astrocytes. Phylogenetic and protein structure analyses of Nef sequences derived from HIV/AIDS patients with and without HAD suggested viral evolution toward a neurotropic Nef protein. These results indicate that HIV-1 Nef contributes to neuropathogenesis by directly causing astrocyte death together with indirect neuronal death through the cytotoxic actions of IP-10 on neurons. Furthermore, Nef molecular diversity was evident in brain tissue among patients with neurological disease and which may influence IP-10 production by astrocytes. |
| Databáze: | OpenAIRE |
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